Kapetsitabin-LF

General characteristics. Structure:

Active ingredient: 150 mg or 250 mg of a kapetsitabin.

Excipients: croscarmellose sodium, cellulose microcrystallic, hydroxypropyl cellulose, magnesium stearate, lactoses monohydrate.

Structure of a cover of capsules: gelatin, titanium dioxide (Е 171), quinolinic yellow (Е 104), orange yellow (Е 110), patent blue V (Е 131), an azoruby E 122, crimson 4R (Е 124), the water purified.

The antineoplastic drug used in oncology.

Pharmacological properties:

Pharmacodynamics. Kapetsitabin – derivative a ftorpirimidina of a carbamate, peroral cytostatics, activated in fabric of a tumor and having the selection cytotoxic effect on it. In vitro капецитабин has no cytotoxic effect, in vivo turns in 5-ftoruratsit (5-FU) which is exposed to a further metaboliz. Education 5-FU happens preferential in tumor fabric under the influence of a tumoral angiogenic factor – thymidinephosphorylases that minimizes system influence 5-FU on healthy body tissues. Consecutive fermental biotransformation of a kapetsitabin in 5-FU creates higher concentration of drug in tumor fabrics, than in surrounding healthy fabrics. After peroral purpose of a kapetsitabin a sick colorectal cancer (N=8) concentration 5-FU in fabric of a tumor is 3,2 times more than its concentration in adjacent healthy fabrics (range from 0,9 to 0,8). Ratio of concentration 5-FU in fabric of a tumor and plasma – 21,4 (range from 3,9 to 59,9), a ratio of its concentration healthy fabrics and in plasma – 8,9 (range 3,0 to 25,8). Activity of thymidinephosphorylase in primary colorectal tumor is also 4 times higher, than in adjacent healthy fabrics.

Tumor cells at patients with cancer of a mammary gland, stomach, a colorectal cancer, a neck of uterus and ovaries contain higher level of thymidinephosphorylase capable to turn 5-DFUR (5-dezoksi-5-ftoruridin) in 5-FU, than in the corresponding healthy fabrics. Both healthy, and tumor cells metabolize 5-FU in 5-fluorine-2-dezoksiuridinmonofosfat (ФдУМФ) and 5-ftoruridintrifosfat (FUTF). These metabolites damage cells by means of two various mechanisms. First, FDUMF and folatny cofactor K5-10-metilentetragidrofolat contact with timidilatsintazy (CU) formation covalently of the connected tertiary complex. This binding suppresses formation of thymidylate from uracil. Thymidylate is a necessary predecessor thymidine of triphosphate which, in turn, is extremely important for DNA synthesis so the lack of this substance can lead to oppression of cellular division. Secondly, in the course of RNA synthesis transkriptsionny enzymes of a kernel can mistakenly include in it FUTF instead of uridinetriphosphate (UTF). This metabolic "mistake" breaks processing of RNA and synthesis of protein.

Pharmacokinetics. After intake капецитабин it is soaked up quickly and completely then there is its transformation in metabolites of 5-dezoksi-5-ftortsitidin (5-DFTsT) and 5-DFUR. Food reduces the speed of absorption of a kapetsitabin, however under a curve "concentration time" (AUC) 5-DFUR and the following metabolite 5-FU influences area size slightly. At purpose of a kapetsitabin after meal in a dose of 1250 mg/sq.m for 14-ny day the maximum concentration in plasma (Cmax) of a kapetsitabin, 5-DFUR, 5-FU and FBAL made respectively: 4,47; 3,05; 12,1; 0,95 and 5,46 mkg/ml. Time of achievement of the maximum concentration (Tmax) equaled 1,50; 2,00; 2,00; 2,00 and 3,34 h AUC 0-∞ were made by 7,75; 7,24; 24,6; 2,03 and 36,3 ¼¬ú*þ/ml, respectively.

Distribution. Showed the researches in vitro in a blood plasma of the person that for a kapetsitabin, 5-DFTsT, 5-DFUR and 5-FU communication with proteins (mainly, with albumine) makes 54%, 10%, 62% and 10%, sootvestsvenno.

Metabolism. It is initially metabolized in a liver under the influence of a karboksilesteraza to a metabolite 5-DFTsT which then is transformed in 5-DFUR under the influence of the cytidinedeaminase which is in the basic in a t liver tumoral fabrics. Further transformation to an active cytotoxic metabolite 5-FU happens preferential in tumor fabric under the influence of a tumoral angiogenic factor of thymidinephosphorylase. AUC for 5-FU in plasma is 6-22 times less, than after intravenous bolyusny administration 5-FU in a dose of 600 mg/sq.m. metabolites of a kapetsitabin become cytotoxic only after transformation in 5-FU and metabolites 5-FU. Further 5-FU catabolizes with formation of inactive metabolites: dihydro-5-ftoruratsila (FUN2), 5-ftorureidopropionovy acid (FUPK) and alpha fluorine - beta alanine (FBAL); this process happens under the influence of a dihydropyrimidindehydrogenase (DPD) which activity limits speed of response.

Removal. Biological half-life (T 1/2) of a kapetsitabin, 5-DFTsR, 5-DFUR, 5-FU and FBAL makes 0,85; 1,11; 0,66; 0,76 and 3,23 hours, respectively. Pharmacokinetics of a kapetsitabin studied in doses from 502 to 3514 mg/sq.m a day. Pharmacokinetic parameters of a kapetsitabin, 5-DFTsT and 5-DFUR for the 1st and 14th day were identical. AUC 5-FU increased by 14th day by 30-35% and did not increase any more (the 22nd day). In the range of therapeutic doses pharmacokinetic parameters of a kapetsitabin and its metabolites, except for 5-FU, had dozozavisimy character. After reception of a kapetsitabin in its metabolites are removed mainly with urine. The most part (95%) of the accepted dose of a kapetsitabin is removed with urine. Removal with a stake is minimum (2,6%). The main metabolite in FBAL urine of which 57% of the accepted dose are the share. About 3% of the accepted dose are removed with urine in an invariable look.

Combination therapy. Any impact of drug on pharmacokinetics of a dotsetaksel or a paklitaksel (Cmax and AUC), and also or paklitakset influences of a dotsetaksel on pharmacokinetics 5-DFUR (the main metabolite of a kapetsitabin) it is not revealed.

Pharmacokinetics in special clinical groups. A floor, existence or lack of metastasises in a liver prior to treatment, the index of the general condition of the patient, concentration of the general bilirubin, seralbumin, activity of nuclear heating plant and ALT did not render statistically significant effect on pharmacokinetic properties 5-DFUR, 5-FU and FBAL.

Patients with hepatic insufficiency of the liver caused by metastatic defeat. At patients with easy and moderate degree of the abnormal liver functions caused by metastasises, clinically significant change of bioactivation and pharmacokinetics of a kapetsitabin does not happen. Data on pharmacokinetics at patients with a heavy abnormal liver function are absent.

Patients with a renal failure. Results of a pharmacokinetic research show that at various degree (from easy to heavy) a renal failure the pharmacokinetics of not changed drug and 5-FU does not depend on the clearance of creatinine (CC). KK influences size of AUC 5-DFUR – the direct predecessor 5-FU (increase in AUC by 35% at decrease in KK by 50%) and FBAL (increase in AUC by 114% at decrease in KK by 50%). FBAL – the metabolite which does not have antiproliyerativny activity; 5-DFUR – the direct predecessor 5-FU.

Patients of advanced age. The age does not influence pharmacokinetics 5-DFUR and 5-FU. AUC FBAL increased with age (increase in age of patients by 20% was followed by increase in AUC FBAL by 15%) that is probably caused by change of function of kidneys.

Race. The drug pharmacokinetics at patients of negroid race does not differ from that at patients of Caucasian race.

Indications to use:

1. Breast cancer:
- a combination therapy with dotsetaksely a locally-spread or metastatic breast cancer at inefficiency of the chemotherapy including drug of an intratsiklinovy row.
- monotherapy of a locally-spread or metastatic breast cancer resistant to chemotherapy taxons or drugs of an anthracycline row or in the presence of contraindications to them.
2. Colorectal cancer:
- adjuvant therapy of a colon cancer of the III stage after surgical treatment
- therapy of a metastatic colorectal cancer.
3. Carcinoma of the stomach:
- therapy of the first line of a widespread carcinoma of the stomach.

Route of administration and doses:

Inside, washing down with water not later than in 30 minutes after food.

Monotherapy. Colorectal cancer, colon cancer, breast cancer. On 1250 mg/sq.m twice a day – in the morning and in the evening (the general daily dose of 2500 mg/sq.m) within two weeks with the subsequent seven-day break.

Combination therapy. Breast cancer. On 1250 mg/sq.m twice a day within two weeks with the subsequent seven-day break, in a combination with dotsekaly in a dose of 75 mg/sq.m once in three weeks in the form of intravenous infusion within 1 hour. Premedication is carried out before introduction of a dotsetaksel according to the instruction for its use.

Colorectal cancer and carcinoma of the stomach. As a part of a combination therapy the dose of drug has to be lowered to 800-1000 mg/sq.m twice a day within two weeks with the subsequent seven-day a break or to 625 mg/sq.m twice a day at the neprervyny mode. Addition of immunobiological drugs to a combination therapy does not influence a drug dose.

In adjuvant therapy of a colon cancer the recommended therapy duration drug makes 6 months, i.e. 8 courses.

Antiemetics and premedication for ensuring adequate hydration are appointed before introduction of a tsiplastin according to application instructions of a tsiplastin and oksaliplatin.

The tables given below show the examples of a rachet of a standard and reduced dose of 1250 mg/sq.m calculated depending on body surface area.

	Dose – on 1250 mg/sq.m
	Full dose of 1250 mg/sq.m	Number of capsules of 150 mg and/or 250 mg on reception (on each reception twice a day – in the morning and in the evening)		Reduced dose (75% of an initial dose) of 950 mg/sq.m	Reduced dose (50% of an initial dose) of 625 mg/sq.m
Surface area of a body (sq.m)	Dose on reception (mg)	150 mg	250 mg	Dose on reception (mg)	Dose on reception (mg)
≤ 1,26	1500	-	6	1150	800
1,26-1,38	1650	1	6	1300	800
1,39-1,52	1800	2	6	1450	950
1,53-1,66	2000	-	8	1500	1000
1,67-1,78	2150	1	8	1650	1000
1,79-1,92	2300	2	8	1800	1150
1,93-2,06	2500	-	10	1950	1300
2,07-2,18	2650	1	10	2000	1300
≥ 2,19	2800	2	19	2150	1450

Table 2. Standard and the reduced doses of drug Kapetsitabin-LF for an initial dose of 1000 mg/sq.m calculated depending on body surface area.

	Dose – on 1250 mg/sq.m
	Full dose of 1250 mg/sq.m	Number of capsules of 150 mg and/or 250 mg on reception (on each reception twice a day – in the morning and in the evening)		Reduced dose (75% of an initial dose) of 950 mg/sq.m	Reduced dose (50% of an initial dose) of 625 mg/sq.m
Surface area of a body (sq.m)	Dose on reception (mg)	150 mg	250 mg	Dose on reception (mg)	Dose on reception (mg)
≤ 1,26	1150	1	4	800	600
1,26-1,38	1300	2	4	1000	600
1,39-1,52	1450	3	4	1100	750
1,53-1,66	1600	4	4	1200	800
1,67-1,78	1750	5	4	1300	800
1,79-1,92	1800	2	6	1400	900
1,93-2,06	2000	-	8	1500	1000
2,07-2,18	2150	1	8	1600	1050
≥ 2,19	2300	2	8	1750	1100

Scheme of dose adjustment of drug Kapetsitabin-LF.
Change of a dose during a therapy cycle.

At 1 degree of toxicity of NCIC * - to continue treatment in the same dose.

At degree 2:
- the 1st emergence, the 2nd emergence, the 3rd emergence - to interrupt therapy up to the permission to degree 0-1; the 4th emergence - completely to stop therapy.

At degree 3.
- the 1st emergence, the 2nd emergence - to interrupt therapy up to the permission to degree 0-1; the 3rd emergence - completely to stop therapy.

At degree 4.
- the 1st emergence - completely to stop therapy or if the doctor considers that for the benefit of the patient to continue treatment, to interrupt therapy up to the permission to degree 0-1; the 2nd emergence - completely to stop therapy.

Dose adjustment during the following cycle of therapy (% of an initial dose).
Degree 1. To continue in the same dose.
Degree 2.
- the 1st emergence – 100%
- the 2nd emergence – 75%
- the 3rd emergence – 50%
- the 4th emergence – completely to stop therapy.

Degree 3.
- the 1st emergence – 75%
- the 2nd emergence – 50%
- the 3rd emergence – is not applicable.

Degree 4.
- the 1st emergence – 50%
- the 2nd emergence – is not applicable.
* In compliance with the general criteria of toxicity of Group on conduct of clinical trials of National oncological institute of Canada (NCIC CTG, version 1) or the general terminological criteria of the undesirable phenomena of the Program for assessment of antineoplastic therapy of National oncological institute of the USA (CTCAE, version 3).

Dose adjustment at development of side effects. General recommendations. The toxic phenomena of drug can be eliminated with symptomatic therapy and/or dose adjustment of drug (having interrupted treatment or we will reduce a drug dose). If the dose had to be lowered, its vposledsviya cannot increase. If according to the attending physician the toxic effect of drug has no serious or life-threatening sick character, treatment can be continued in an initial dose without its reduction or interruption of therapy. At toxicity of the 1st degree the dose is not changed. At toxicity of the 2nd or 3rd degree therapy by drug should be interrupted. At disappearance of signs of toxicity or reduction of the last to the 1st degree, performing therapy by drug can be resumed in a full dose or is corrected according to the recommendations specified in table 3. At development of signs of toxicity of the 4th degree treatment should be stopped or to interrupt temporarily before stopping or reduction of symptoms to the 1st degree then use of drug can be resumed in the dose making 50% of initial.

The patient has to report to the doctor about the undesirable phenomena which developed at him immediately. It is necessary to stop immediately administration of drug at emergence of toxicity heavy or moderate severity. If because of toxicity of the phenomena several administrations of drug were missed, then these doses are not filled.

Hematologic toxicity. Therapy by drug should be interrupted at detection of signs of gematologichsky toxicity of the 3rd or 4th degree.

The general recommendations at a combination therapy. In case of the phenomena of toxicity when carrying out a combination therapy it is necessary to adhere to the recommendations about drug dose adjustment Kapetsitabin-LF stated above in table 3 and the corresponding recommendations in application instructions of other drugs. At the beginning of a therapy cycle if the delay with administration of drug or other drug(s) is expected, it is necessary to postpone reception of all drugs until conditions for therapy resuming are reached by all drugs.

If during a cycle of a combination therapy of the phenomenon of toxicity, according to the doctor, are not connected using drug Kapetsitabin-LF, then therapy by drug should be continued, and to adjust a dose of other drug according to recommendations of the instruction for its use. If other drug(s) has to be cancelled, drug Kapetsitabin-LF can continue treatment at satisfaction requirements for therapy resuming by drug. These recommendations are applicable concerning all testimonies and all special groups of patients.

Dose adjustment in special cases. An abnormal liver function at patients with metastasises in a liver. Change of an initial dose is not required from patients with metastasises in a liver and easy or moderate abnormal liver functions. However these patients should be observed carefully. Use of drug for patients with a heavy liver failure was not studied.

Renal failure. Reduction of an initial dose to 75% of 1250 mg/sq.m at patients with an initial moderate renal failure is recommended (KK of 30-50 ml/min., on a formula Cockroft-Gault). With easy degree of a renal failure (KK of 51-80 ml/min.) correction of an initial dose is not required from patients. In case of emergence at the patient of the undesirable phenomenon of the 2nd, 3rd or 4th severity, its careful monitoring and an immediate break of the carried-out therapy for the purpose of the subsequent dose adjustment of drug according to the recommendations specified in table 3 is necessary.

If the calculated clearance of creatinine decreased during performing therapy to level less than 30 ml/min., therapy by drug should be stopped. Recommendations about dose adjustment of drug at a moderate renal failure belong both to monotherapy, and to a combination therapy.

Calculation of a dose is specified in tables 1 and 2.

Children. Safety and efficiency of drug at children was not studied.

Patients of advanced and senile age. Correction of an initial dose at monotherapy by drug is not required. However the heavy undesirable phenomena of the 3rd and 4th degree connected with the carried-out therapy developed at patients 80 years are more senior more often than at young people. When using drug in a combination with other antineoplastic drugs at elderly patients (65 years are more senior) undesirable reactions of the 3rd and 4th severity, and also the undesirable reactions which demanded therapy cancellation were noted more often than at more young people. Careful monitoring of a condition of patients of advanced age is recommended.

At treatment in a combination with dotsetaksely at patients at the age of 60 years is also more senior it was noted uvelichesny frequencies of the undesirable phenomena of the 3rd and 4th degree and the serious undesirable phenomena connected with therapy. For patients at the age of 60 years is also more senior which will receive a drug combination Kametsitabin_lf with dotsetaksely, it is recommended to lower an initial dose of drug to 75% (950 mg/sq.m twice a day). Calculation of a dose is given in table 2. at treatment in a combination with irinotekany at patients at the age of 65 years is also more senior it is recommended to lower an initial dose of drug to 800 mg/sq.m twice a day.

Features of use:

Drug is contraindicated to use during pregnancy and in the period of a location (GV).

During treatment careful medical control for the purpose of early detection of signs of toxicity is necessary (diarrhea, nausea, stomatitis, a neutropenia, etc.). at emergence of toxic symptoms, depending on their expressiveness, performing symptomatic therapy, a dose decline is possible, having rummaged in treatment or full cancellation.

Diarrhea: treatment by drug can cause diarrhea, sometimes heavy. Patients with heavy diarrhea should be observed carefully, and at development of dehydration it is necessary to carry out a regidratation or compensation of loss of electrolytes. It is necessary to appoint standard antidiarrheal drugs (for example, loperamide) on medical indications as soon as possible. If necessary it is necessary to reduce a drug dose.

Dehydration: dehydration should be warned or eliminated at the very beginning of emergence. Dehydration can quickly develop at patients with an anorektion, an adynamy, nausea, vomiting or diarrhea. At development of dehydration 2 degrees or above, treatment it is necessary to interrupt and carry out by drug a regidratation immediately. Treatment cannot be resumed before end of a regidratation and elimination or correction of the factors which caused it. The dose of drug should be modified according to recommendations for the undesirable phenomena which led to dehydration.

The cardiotoxicity range at treatment kapetsitabiny is similar to that when using other ftorpirimidin and includes a myocardial infarction, stenocardia, arrhythmias, a cardiac standstill, heart failure and changes on an ECG. These undesirable phenomena are more characteristic of the patients suffering from an ischemic heart disease.

In rare instances the unexpected heavy phenomena of toxicity (for example, stomatitis, diarrhea, a neutropenia and a neurotoxicity) associated with 5-FU are caused by insufficient activity of a dihydropyrimidindehydrogenase (DPD). Thus, it is impossible to exclude communication between reduced activity of DPD and more expressed, potentially lethal toxicity 5-FU.

Manifestation of skin toxicity of drug is development of a palmar and bottom syndrome (synonyms – the palmar and bottom eritrodizesteziya or an akralny erythema caused by chemotherapy). Time median before development of manifestations of toxicity in patients, receiving monotherapy by drug, makes 79 days (in the range from 11 to 360), and severity varies from the 1st degree to the 3rd degree. Palmar and bottom the syndrome of the 1st degree does not break daily activity of the patient and is shown by numbness, дизестезиями / paresthesias, a pricking or reddening of palms and/or soles, discomfort. Palmar подошвенно the syndrome of the 2nd degree is characterized by painful reddening and hypostases of brushes and/or feet, and the discomfort caused by these symptoms breaks daily activity of the patient. The palmar and bottom syndrome of the 3rd degree is defined as wet desquamation, an ulceration, formation of bubbles and sharp pains in brushes and/or feet, and also the strong discomfort making impossible for the patient any kinds of daily activity. At emergence of a palmar and bottom syndrome of the 2nd or 3rd degree therapy by drug should be interrupted before disappearance of symptoms or their reduction to the 1st degree. At emergence of a syndrome of the 3rd degree the subsequent doses of drug have to be reduced.

B6 vitamin (pyridoxine) is not recommended to be applied to symptomatic or secondary preventive treatment of a palmar and bottom syndrome at purpose of drug in a combination with Cisplatinum as it can reduce efficiency of Cisplatinum.

Drug can cause a hyperbilirubinemia. If in connection with treatment drug notes a hyperbilirubinemia> 3,0khvgn (the upper bound of norm) or increase in activity of hepatic aminotransferases (ALT, nuclear heating plant)> 2,5khvgn, treatment should be interrupted. Performing therapy can be resumed at decrease in level of bilirubin and activity of hepatic aminotransferases below the specified limits.

At the patients who are at the same time accepting drug Kapetsitabin-LF and peroral anticoagulants – coumarin derivatives, it is necessary to control coagulability indicators (a prothrombin time or MNO) and according to it to select an anticoagulant dose.

Use of drug for patients of advanced and senile age. Frequency of the toxic phenomena from a GIT at patients with a colorectal cancer at the age of 60-79 years receiving monotherapy by drug did not differ from that in the general population of patients. Patients have 80 years and the reversible undesirable phenomena from a GIT of the 3rd and 4th degree are more senior, such as diarrhea, nausea, vomiting, developed more often. At patients> 65 years receiving a combination therapy kapetsitabiny and other antineoplastic drugs, were celebrated increase in frequency of undesirable reactions of the 3rd and 4th severity and the undesirable phenomena which led to the termination of therapy in comparison with patients of younger age. In the analysis of data of safety at patients> 60 years receiving a combination therapy drug Kapetsitabin-LF and dotsetaksely are celebrated increase in frequency connected, with therapy of the undesirable phenomena and early cancellation of therapy and - for undesirable in comparison with those at patients 60 years are younger than the phenomena.

Renal failure. It is necessary to be careful at purpose of drug to patients with a renal failure of moderate severity. As well as at treatment ftoruratsily, the frequency of development connected with the carried-out therapy of the undesirable phenomena of the 3rd and 4th severity was higher at patients with a renal failure of moderate severity (clearance of creatinine of 30-50 ml/min.).

Liver failure. Patients with a liver failure during therapy by drug have to be under careful medical observation. Influence of an abnormal liver function, the liver which is not caused by metastatic defeat or a heavy liver failure, on distribution of drug is unknown.

During therapy by drug and at least within 3 months after its termination it is necessary to use reliable methods of contraception. If pregnancy occurred during performing therapy, the patient has to be informed on potential threat for a fruit.

Side effects:

Frequency of undesirable reactions which were observed or during conduct of clinical trials or were received from spontaneous messages on development of undesirable reactions is defined as follows: often (> 1/100 - <1/10); infrequently (> 1/1000 - <1/100); seldom (> 1/10 000 - <1/1000); very seldom (<1/10 000), it is unknown (frequency cannot be determined by the data which are available for today).

From a metabolism: very often – anorexia; often – dehydration, a loss of appetite.

From a nervous system: often – a headache, dizziness (except вертиго), paresthesia, a dysgeusia (food faddism).

From an organ of sight: often – the raised slezootdeleniye, conjunctivitis.

From system of digestion: very often – diarrhea, vomiting, nausea, stomatitis (including ulcer), abdominal pains; often – a lock, pains in epigastriums, dyspepsia.

From integuments: very often – a palmar and bottom syndrome (paresthesias, hypostasis, a hyperemia, a skin peeling, blistering), dermatitis; often – rash, an alopecia, an erythema, a xeroderma, blistering), dnrmatit; often – rash, an alopecia, an erythema, a xeroderma. At less than 2% of patients in 7 complete clinical trials (N=949) it was reported about skin cracks, at least, presumably connected with therapy by drug.

Changes of laboratory indicators: often – a hyperbilirubinemia.

Others: very often – increased fatigue, the increased drowsiness; often – fever, weakness, an adynamy.

The following undesirable reactions are the toxicity manifestations known for therapy of a ftorpirimidinama; it was reported, at least, about indirect communication between development of such reactions and use of drug at less than 5% of the patients participating in 7 complete clinical trials (N=949):
- from the alimentary system: dryness in a mouth, the meteorism, undesirable reactions connected with an inflammation/ulceration of mucous membranes such, as: esophagitis, gastritis, duodenitis, colitis, gastrointestinal bleeding;
- from CCC: hypostases of the lower extremities, cardialgias, including stenocardia, a cardiomyopathy, myocardium ischemia, a myocardial infarction, heart failure, sudden death, tachycardia, supraventricular arrhythmias, including fibrillation of auricles, ventricular extrasystoles;
- from a nervous system: taste disturbance, sleeplessness, confusion of consciousness, encephalopathy, symptoms of cerebellar disturbances (ataxy, dysarthtia, disturbance of balance and coordination);
- from the mental sphere: depressions;
- infections: the infectious complications connected with a miyelosupressiya, easing of immunity and/or disturbances of integrity of mucous membranes such as local and fatal system infections (bacterial, virus or fungal etiology) and sepsis;
- from system of bodies of a hemopoiesis: anemia, миелосупрессия / pancytopenia;
- from integuments: an itch, a focal peeling of skin, a hyperpegmentation of skin, change of nails, reactions of a photosensitization, the syndrome reminding beam dermatitis;
- from an organ of sight: irritation of eyes;
- from respiratory system: short wind, cough;
- from a musculoskeletal system: arthralgia, mialgiya, dorsodynia;
- others: an adynamy, a stethalgia (not cardial etiology), extremity pain, the increased drowsiness.

In clinical trials and in the post-marketing period cases of a liver failure and cholestatic hepatitis were registered. Relationship of cause and effect is not established with administration of drug.

At therapy by drug in a combination with other chemotherapeutic drugs often (but not less, than at 5% of patients) it was reported about cases of reactions of hypersensitivity (2%) and an ischemia/myocardial infarction (3%).

Changes from laboratory indicators. The changes of laboratory indicators observed at 995 patients at therapy of a metastatic colon cancer and at 949 patients at therapy of a metastatic breast cancer and metastatic colorectal cancer regardless of their communication with administration of drug are given below: neutropenia, granulocytopenia, lymphocytopenia, thrombocytopenia, anemia, hyperbilirubinemia, increase in activity of ALT, nuclear heating plant, alkaline phosphotazy, giperkreatininemiya, гипо-/hypercalcemia, hyperglycemia, hyponatremia, hypopotassemia.

Post-marketing observation. During post-marketing use of drug the following undesirable reactions are found:
- very seldom – the stenosis of the lacrimal tubule which is not specified;
- very seldom – in clinical trials and in the post-marketing period cases of a liver failure and cholestatic hepatitis were registered.

Interaction with other medicines:

Anticoagulants of a coumarinic row. At the patients accepting drug along with anticoagulants of a coumarinic row (warfarin and фенпрокумон), it was reported about disturbances of indicators of coagulation and/or bleedings in several days or months from the beginning of therapy kapetsitabiny, and in several cases – within one month after its end.

In a research of medicinal interaction after single administration of warfarin in a dose of 20 mg drug increased AUC of S-warfarin by 57%, and the size of the international normalized relation (MNO – for 91%. At the patients who are at the same time accepting drug anticoagulants of a coumarinic row it is necessary to watch carefully coagulability indicators (a prothrombin time or MNO), the dose of anticoagulant should be selected according to these indicators.

P4502C9 cytochrome substrates. Special researches of medicinal interaction of a kapetsitabin with other drugs which are metabolized an isoenzyme 2C9 of system of P450 cytochrome were not conducted. It is necessary to be careful at purpose of drug Kapetsitabin-LF together with these drugs.

Phenytoinum. At a concomitant use of drug and Phenytoinum it was reported about increase in concentration of the last in plasma. Special researches of intermedicinal interaction of drug and Phenytoinum were not conducted, however it is supposed that suppression of an isoenzyme of CYP2C9 under the influence of a kapetsitabin is the cornerstone of the mechanism of interaction. At the patients receiving at the same time Phenytoinum and drug it is regularly necessary to control concentration of Phenytoinum in plasma.

Antacids. At assessment of pharmacokinetic parameters of a preaparat at a concomitant use with the antacids containing aluminum hydroxide and magnesium hydroxide small increase in concentration of a kapetsitabin and one of metabolites (5-DFTsT) in a blood plasma is noted. The studied means did not exert impact on three main metabolites of a kapetsitabin (5-DFUR, 5-FU and FBAL).

Calcium фолинат (лейковорин). Calcium фолинат does not influence pharmacokinetic properties of a kapetsitabin and its metabolites. However, strengthening of toxic effect of a kapetsitabin due to influence of calcium of a folinat on a drug pharmacodynamics is possible.

Sorivudin and his analogs. In references clinically significant medicinal interaction of a sorivudin and 5-FU which cornerstone the inhibiting effect of a sorivudin on DPD is is described. The specified interaction can lead to fatal strengthening of toxicity of ftorpirimidin. Therefore it is not necessary to appoint drug along with sorivudiny or its structural analogs like brivudin. It is necessary to observe at least a four-week interval between the end of therapy sorivudiny or its structural analogs (including бривудин) and an initiation of treatment drug.

Oksaliplatin. Clinically significant difference in exposure of a kapetsitabin or metabolites of an oksaliplatin (free platinum or the general platinum) at the combined use of a kapetsitabin and oksaliplatin, irrespective of presence of a bevatsizumab, is noted.

Bevatsizumab. Clinically significant effect of a bevatsizumab on pharmacokinetics of a kapetsitabin or its metabolites is noted.

Contraindications:

• hypersensitivity to a kapetsitabin and other derivatives of a ftorpirimidin or any components of drug;
• the established deficit of a dihydropyrimidindehydrogenase;
• concomitant use of a sorivudin and its structural analogs (for example, brivudina);
• a renal failure of heavy degree (the clearance of creatinine is lower than 30 ml/min.);
• initial maintenance of neutrophils <1,5Õ109/l and/or thrombocytes <100kh109l;
• pregnancy and period of a lactation;
• children's and teenage age up to 18 years.

With care it is necessary to appoint drug at an ischemic heart disease, a renal or liver failure, along with peroral anticoagulants of a coumarinic row, hereditary deficit of lactase, a lactose intolerance, glyukozogalaktozny malabsorption, and also to patients 60 years are aged more senior.

Overdose:

Symptoms of acute overdose include nausea, vomiting, diarrhea, the inflammation of a mucous membrane (mukozit), irritation of a GIT and bleeding, and also oppression of function of marrow.

Treatment of overdose has to include a standard complex of the therapeutic and supporting actions directed to correction of clinical symptoms and the prevention of possible complications.

Storage conditions:

To store in protected from moisture and light the places not available to children, at a temperature not above 25 °C. Period of validity 2 years.

Issue conditions:

According to the recipe

Packaging:

On 10 capsules in blister strip packagings from a film of polyvinyl chloride and aluminum foil. On 6 or 12 blister strip packagings in cardboard packs together with the application instruction.